Type II aromatic polyketide biosynthetic tailoring enzymes: diversity and adaptation in Streptomyces secondary metabolism.

Members of the bacterial genus Streptomyces are well known for their ability to produce an exceptionally wide selection of diverse secondary metabolites. These include natural bioactive chemical compounds which have potential applications in medicine, agriculture and other fields of commerce. The outstanding biosynthetic capacity derives from the characteristic genetic flexibility of Streptomyces secondary metabolism pathways: i) Clustering of the biosynthetic genes in chromosome regions redundant for vital primary functions, and ii) the presence of numerous genetic elements within these regions which facilitate DNA rearrangement and transfer between non-progeny species. Decades of intensive genetic research on the organization and function of the biosynthetic routes has led to a variety of molecular biology applications, which can be used to expand the diversity of compounds synthesized. These include techniques which, for example, allow modification and artificial construction of novel pathways, and enable gene-level detection of silent secondary metabolite clusters. Over the years the research has expanded to cover molecular-level analysis of the enzymes responsible for the individual catalytic reactions. In vitro studies of the enzymes provide a detailed insight into their catalytic functions, mechanisms, substrate specificities, interactions and stereochemical determinants. These are factors that are essential for the thorough understanding and rational design of novel biosynthetic routes. The current study is a part of a more extensive research project (Antibiotic Biosynthetic Enzymes; www.sci.utu.fi/projects/biokemia/abe), which focuses on the post-PKS tailoring enzymes involved in various type II aromatic polyketide biosynthetic pathways in Streptomyces bacteria. The initiative here was to investigate specific catalytic steps in anthracycline and angucycline biosynthesis through in vitro biochemical enzyme characterization and structural enzymology. The objectives were to elucidate detailed mechanisms and enzyme-level interactions which cannot be resolved by in vivo genetic studies alone. The first part of the experimental work concerns the homologous polyketide cyclases SnoaL and AknH. These catalyze the closure of the last carbon ring of the tetracyclic carbon frame common to all anthracycline-type compounds. The second part of the study primarily deals with tailoring enzymes PgaE (and its homolog CabE) and PgaM, which are responsible for a cascade of sequential modification reactions in angucycline biosynthesis. The results complemented earlier in vivo findings and confirmed the enzyme functions in vitro. Importantly, we were able to identify the amino acid -level determinants that influence AknH and SnoaL stereoselectivity and to determine the complex biosynthetic steps of the angucycline oxygenation cascade of PgaE and PgaM. In addition, the findings revealed interesting cases of enzyme-level adaptation, as some of the catalytic mechanisms did not coincide with those described for characterised homologs or enzymes of known function. Specifically, SnoaL and AknH were shown to employ a novel acid-base mechanism for aldol condenzation, whereas the hydroxylation reaction catalysed by PgaM involved unexpected oxygen chemistry. Owing to a gene-level fusion of two ancestral reading frames, PgaM was also shown to adopt an unusual quaternary sturucture, a non-covalent fusion complex of two alternative forms of the protein. Furthermore, the work highlighted some common themes encountered in polyketide biosynthetic pathways such as enzyme substrate specificity and intermediate reactivity. These are discussed in the final chapters of the work.

Tailoring of health information

Abstrakti

Structural and functional Studies of angucycline tailoring enzymes

Polyketides are a diverse group of natural products produced in many bacteria, fungi and plants. These metabolites have diverse biological activities and several members of this group are in clinical use as antibiotics, anticancer agents, antifungals and immunosuppressants. The different polyketides are produced by polyketide synthases, which catalyze the condensation of extender units into various polyketide scaffolds. After the biosynthesis of the polyketide backbone, more versatility is created to the molecule by tailoring enzymes catalyzing for instance hydroxylations, methylations and glycosylations. Flavoprotein monooxygenases (FPMO) and short-chain alcohol dehydrogenases/reductases (SDR) are two enzyme families that catalyze unusual tailoring reactions in the biosynthesis of natural products. In the experimental section, functions of homologous FPMO and SDR tailoring enzymes from five different angucycline pathways were studied in vitro. The results revealed how different angucyclinones are produced from a common intermediate and that FPMO JadH and SDR LanV are responsible for the divergence of jadomycins and landomycins, respectively, from other angucyclines. Structural studies of these tailoring enzymes revealed differences between homologous enzymes and enabled the use of structure-based protein engineering. Mutagenesis experiments gave important information about the enzymes behind the evolution of distinct angucycline metabolites. These experiments revealed a correlation between the substrate inhibition and bi-functionality in JadH homologue PgaE. In the case of LanV, analysis of mutagenesis results revealed that the difference between the stereospecificities of LanV and its homologues CabV and UrdMred is unexpectedly related to the conformation of the substrate rather than to the structure of the enzyme. Altogether, the results presented here have improved our knowledge about different steps of angucycline biosynthesis and the reaction mechanisms used by the tailoring enzymes behind these steps. This information can hopefully be used to modify these enzymes to produce novel metabolites, which have new biological targets or possess novel modes-of-action. The understanding of these unusual enzyme mechanisms is also interesting to enzymologists outside the field of natural product research.

Pelaamisen lumo : tietokoneella pelaaminen terapeuttisena toimintana

Opinnäytetyön tarkoituksena on käsitellä pelaamista toimintana ja tarkastella pelaamista terapeuttisen toiminnan käsitteellisen viitekehyksen kautta. Tavoitteena on löytää perusteita tietokonepelien käyttöön lasten ja nuorten toimintaterapiassa. Opinnäytetyöprosessiani on ohjannut David L. Nelsonin ja Julie Jepson-Thomasin Terapeuttisen toiminnan käsitteellinen viitekehys. Viitekehyksen avulla tutkin millaista terapeuttista toimintaa pelaaminen on. Opinnäytetyön teoriapohja perustuu eri ammattialojen yleisiin pelitutkimuksiin, koska tietokoneella pelaamisen terapeuttisia vaikutuksia on tutkittu hyvin vähän kuntoutuksen näkökulmasta. Opinnäytetyö on laadullinen. Haastattelin kolmea nuorta poikaa heidän pelikokemuksistaan. Opinnäytetyön teoriasta ja aineistosta löytyi useita pelaamiseen vaikuttavia tekijöitä. Niiden perusteella tietokonepelien käyttö lasten ja nuorten toimintaterapiassa on perusteltua koska pelaaminen on lapsille ja nuorille tärkeää ja hyvin motivoivaa toimintaa. Se on merkittävä terapeuttinen tekijä sekä asiakaskeskeisen työskentelytavan ydin. Terapeuttisen toiminnan käsitteellisen viitekehyksen mukaan toiminnan mukautuminen on sitä kun pelaamalla pelaaja muuttaa itseään. Se antaa terapeutille mahdollisuuden työskennellä asiakkaansa tavoitteiden kanssa asiakkaalle hyvin merkityksellisen toiminnan avulla. Terapeutin ja asiakkaan tarkoitukset toiminnalle voivat olla erilaiset, pelaaminen mahdollistaa ne. Toiminnan mukautumista voi tapahtua kaikessa pelaajan kehityksellisessä rakenteessa: sensomotorisessa, kognitiivisessa ja psykososiaalisessa rakenteessa. Pelitutkijoiden tutkimus tukee johtopäätöstä. Pelaamista voi siten käyttää hyvin monen erilaisen asiakasryhmän kanssa. Pelaaminen myös mahdollistaa tavoitteiden toteutuksen varioinnin, tavoitetta voi harjoitella ja kehittää monilla erilaisilla peleillä. Pelaamisen tärkein terapeuttinen tekijä on eläytymisen mahdollisuus. Pelien avulla voi esimerkiksi liikuntavammainen asiakas kokea liikkumisen iloa. Pelaaminen tarjoaa terapeuttisesti tärkeitä voimaannuttavia tekijöitä. Tietokoneella pelaaminen terapeuttisena toimintana on vain yksi osa tavoitteellista terapiaprosessia, ei koskaan ainoa toiminnan muoto. Terapeuttisena toimintana pelaaminen ei ole itsetarkoitus, vaan se mitä pelaaminen mahdollistaa. Tietokoneen terapeuttisessa käytössä täytyy huomioida ja tiedostaa sen rajoitteet. Tietokoneen käyttäminen ei ole aina helppoa ja se on huomattava taloudellinen ja ajallinen resurssi. Siihen voi liittyä myös tekijöitä jotka vähentävät tai jopa poistavat sen terapeuttista vaikutusta.

Ohjelmistoyritysten liiketoimintamallit Kaakkois-Suomessa

Tutkielman tavoitteena on tunnistaa Kaakkois-Suomen alueella olevat ohjelmistoyritysten tyypilliset yritysryhmät ja kuvata niiden toimintaa. Tunnistamalla alueen ohjelmistoyrityksille ominaiset piirteet työ antaa myös pohjaa tulevien kehityskohteiden löytämisessä ja kehitystoimenpiteiden kohdistamisessa useisiin samantyyppisiin yrityksiin. Työn taustaksi esitellään ohjelmistoalaa ja ohjelmistoliiketoiminnan malleja, joiden pohjalta muodostetaan viitekehys alueen ohjelmistoyritysten empiiriseen tarkasteluun. Empiriaosuudessa tarkastellaan työn teoreettisessa osiossa esitettyjen liiketoimintamallien toteutumista Kaakkois-Suomessa ja ryhmitellään alueen ohjelmistoyritykset erottelevimpien tekijöiden avulla. Tutkimus on luonteeltaan kvantitatiivinen kokonaistutkimus Kaakkois-Suomen ohjelmistoyrityksistä, ja tutkimusotteeltaan deskriptiivinen eli kuvaileva. Tutkimusaineisto perustui tutkimusryhmän suorittamaan strukturoituun haastatteluun, jossa haastateltiin kaikkiaan 58 ohjelmistoyrityksen vastuuhenkilöitä. Tutkimustulosten perusteella alueelta pystyttiin tunnistamaan neljä toimintatavoiltaan erilaista ohjelmistoliiketoiminnan perustyyppiä: asiakaslähtöiset toimijat (26 toimipaikkaa), räätälöijät (14 toimipaikkaa), integroijat (10 toimipaikkaa) ja tuotteistajat (8 toimipaikkaa). Tulokset osoittavat, että perinteisten ohjelmistoalan liiketoimintamallien kuvaukset ja niistä tehtävät yleistykset antavat hyvän lähtökohdan ohjelmistoyritysten tarkasteluun. Kuitenkin perinteisten ohjelmistoalan liiketoimintamallien antama näkökulma on liian rajoittunut,jos halutaan tarkastella syvällisemmin ohjelmistoyritysten liiketoimintalogiikkaa.

Älykäs sisältötuote monimediaympäristössä, case: AVO

Diplomityön teoriaosassa tutkittiin monimedian jakelukanavia ja niiden ominaisuuksia sisältöpalveluissa. Työssä esiteltiin keinoja älykkyyden lisäämiseksi monnimediasisältötuotannossa sekä tarkasteltiin sisältöpalvelujen käytettävyyttä. Työssä keskityttiin neuroverkkoteknologiaan, sen toteuttamiseen sekä ohjelmisto-agentteihin. Empiirisessä osassa tutustuttiin työministeriön AVO-ammatinvalintaohjelman toimintaan. Työssä määriteltiin Excel-taulukkoon 280 ammatin ominaisuudet, jotka pohjautuivat AVO:n 122 kysymykseen. Työministeriöstä on saatu 5115 henkilön vastaukset AVO-ammatinvalintaohjelman kysymyksiin. Tätä vastausaineistoa ja tutkimuksessa laadittua ammattitaulukkoa käytettiin neuroverkon opettamiseen. Lopuksi analysoitiin SOM-karttoja. Analyysin tarkoituksena oli tutkia laaditun ammattitaulukon oikeellisuutta ja eri ammattien sijoittumista SOM-kartalle. Tutkimus osoitti, että neuroverkkoteknologia soveltuisi uuden urasuunnittelupalvelun ydinteknologiaksi.

Strategic supply lead time management. Case Nokia Networks, Hardware Services

Teollisuuden palveluiden on huomattu olevan potentiaalinen lisätulojen lähde. Teollisuuden palveluiden dynaamisessa maailmassa räätälöinti ja kyky toimia nopeasti ovat kriittisiä asiakastyytyväisyyden ja kilpailuedun luomisprosessin osia. Toimitusketjussa käytetyn ajan lyhentämisellä voidaan saavuttaa sekä paremmat vasteajat, että alhaisemmat kokonaiskustannukset. Tutkielman tavoitteena on kuvata teollisuuden palveluiden dynaamista ympäristöä: asiakastarvetta, sekä mahdollisuuksia kaventaa pyydetyn ja saavutetun toimitusajan välistä eroa. Tämä toteutetaan pääosin strategisen toimitusajan hallinnan keinoin. Langattomien tietoliikenneverkkojen operaattorit haluavat vähentää ydinosaamiseensa kuulumatomiin toimintoihin, kuten ylläpitoon sitoutuneita pääomia. Tutkielman case osiossa varaosapalvelujen toimitusketjun kysyntä-, materiaali- ja informaatiovirtoja analysoidaan niin kvalitatiivisten haastatteluiden, sisäisten dokumenttien, kuin kvantitatiivisten tilastollisten menetelmienkin avulla. Löydöksiä peilataan vallitsevaa toimitusketjun ja ajanhallinnan paradigmaa vasten. Tulokset osoittavat, että vahvan palvelukulttuurin omaksuminen ja kokonaisvaltainen toimitusketjun tehokkuuden mittaaminen ovat ajanhallinnan lähtökohtia teollisuuden palveluissa.

Verkostoliiketoiminnan kehittäminen betoniteollisuudessa

Tutkimuksen tarkoituksena oli tutkia päähankkijan ja toimittajien välistä yhteistyötä. Tavoitteena oli selvittää voidaanko verkostoyhteistyötä kehittämällä parantaa kilpailukykyä ja saavuttaa tuotteiden parempaa laatua. Ensin selvitettiin verkoston kehityskeinoja kirjallisuuden avulla. Tämän lisäksi kartoitettiin tutkimuskohteena olleen yrityksen nykytilanne kehityksen lähtökohdaksi. Selvitystöiden perusteella määriteltiin tavoitteet verkostoyhteistyön parantamiseksi sekä luotiin malli, jonka pohjalta kohdeyrityksen toimintaa tullaan kehittämään.

Menestyksekkäät yliopistopelin pelaajat? Tutkimus nopeasti ja nuorena valmistumisesta

Succestul players of the university game? A study about the short duration of master’s degree studies and graduating at a young age The duration of studies has long been a topic of conversation. It was first mentioned in 1883, but the discussion has been quite active and topical for the last fifty years. During that time, there have been numerous committees, working groups for the Ministry of Education, and revisions to the structure of the master’s degree program. All of these have focused on lowering the duration of studies as well as the age at which students graduate. These two factors have been regarded as indicators of efficiency. Achieving these goals is seen to promote the successful transition from studies to work. In addition, the greater time that people spend working is thought to help with the fiscal burden of an aging population. The reasons for prolonged study seem to be: students working during the course of their studies; the actual workload of the studies, which sometimes does not correlate with the calculated workload; problems with the students’ course selections and with their financial support from the government; issues in teaching; and problems with university funding. This study focuses on students’ study experiences, their progress, and the university itself. Of particular interest was the students’ use of different resources—cultural, social, and economical capital. Participants in the study had graduated from the University of Turku between the years of 1999 and 2001 and were divided into two groups: prompt graduates, those who graduated among the fastest 18th percent in their faculty; and those who graduated at a slower pace. A survey (N=499) and interviews (N=69) were among the methods used, along with a compilation of statistics on the students’ duration of studies, the number of modules studied, and marks obtained. Bourdieu’s theory about fields and the games people play in those fields formed the theoretical background of this study. The university was seen to form a playing field with historically and politically changeable rules. The students playing in this field were considered to possess different economical, social, and cultural resources, which they use more or less successfully. Some of the strategies used by students result in gra¬duating at a young age and/or a short duration of study; some do not. This study divided the age of graduation and the duration of study into separate games. This allowed the study to determine the relationship between these two factors and to examine their similarities and differences. The study also focused on the idea of success. Short duration of studies and a young graduation age can be considered, be some, an indication of success in navigating the university field. This study aimed to see if this concept held true or whether these seeming indicators of success have negative side effects. The main result of this study is that, even though the games of duration and age have similarities, they are sufficiently diverse to be considered separate games, which need different resources. To graduate with a short duration of studies, it is important for a student to successfully view and navigate the university field, tailoring one’s studies and extracurricular activities to suit the individual. In the game of youth, the background of the student seemed to be of greater importance. The youngest graduates had spent more time with their parents, who also had higher educational qualifications. They also had higher achievement in their previous studies. This seems to indicate that their background allowed them to assimilate a better understanding of the school and university fields and that playing the university game was natural for them. As for the aspect of success, it seems that there are many ways to define the term. Youth on graduation and short duration of studies can be seen as two indicators of success. Both revealed negative and positive outcomes, even though short duration of studies seemed more often to be connected with positive outcomes. However, it seems that the best indicator for success is the way in which students organize study into their lives to support and suit their needs and abilities to realize a meaningful life and a successful entry into the field of work.

When to Utilize Software as a Service

Cloud computing enables on-demand network access to shared resources (e.g., computation, networks, servers, storage, applications, and services) that can be rapidly provisioned and released with minimal management effort. Cloud computing refers to both the applications delivered as services over the Internet and the hardware and system software in the data centers. Software as a service (SaaS) is part of cloud computing. It is one of the cloud service models. SaaS is software deployed as a hosted service and accessed over the Internet. In SaaS, the consumer uses the provider‘s applications running in the cloud. SaaS separates the possession and ownership of software from its use. The applications can be accessed from any device through a thin client interface. A typical SaaS application is used with a web browser based on monthly pricing. In this thesis, the characteristics of cloud computing and SaaS are presented. Also, a few implementation platforms for SaaS are discussed. Then, four different SaaS implementation cases and one transformation case are deliberated. The pros and cons of SaaS are studied. This is done based on literature references and analysis of the SaaS implementations and the transformation case. The analysis is done both from the customer‘s and service provider‘s point of view. In addition, the pros and cons of on-premises software are listed. The purpose of this thesis is to find when SaaS should be utilized and when it is better to choose a traditional on-premises software. The qualities of SaaS bring many benefits both for the customer as well as the provider. A customer should utilize SaaS when it provides cost savings, ease, and scalability over on-premises software. SaaS is reasonable when the customer does not need tailoring, but he only needs a simple, general-purpose service, and the application supports customer‘s core business. A provider should utilize SaaS when it offers cost savings, scalability, faster development, and wider customer base over on-premises software. It is wise to choose SaaS when the application is cheap, aimed at mass market, needs frequent updating, needs high performance computing, needs storing large amounts of data, or there is some other direct value from the cloud infrastructure.

Defects in Persistent Luminescence Materials

Persistent luminescence materials can store energy from solar radiation or artificial lighting and release it over a period of several hours without a continuous excitation source. These materials are widely used to improve human safety in emergency and traffic signalization. They can also be utilized in novel applications including solar cells, medical diagnostics, radiation detectors and structural damage sensors. The development of these materials is currently based on methods based on trial and error. The tailoring of new materials is also hindered by the lack of knowledge on the role of their intrinsic and extrinsic lattice defects in the appropriate mechanisms. The goal of this work was to clarify the persistent luminescence mechanisms by combining ab initio density functional theory (DFT) calculations with selected experimental methods. The DFT approach enables a full control of both the nature of the defects and their locations in the host lattice. The materials studied in the present work, the distrontium magnesium disilicate (Sr₂MgSi₂O₇) and strontium aluminate (SrAl₂O₄) are among the most efficient persistent luminescence hosts when doped with divalent europium Eu²⁺ and co-doped with trivalent rare earth ions R³⁺ (R: Y, La-Nd, Sm, Gd-Lu). The polycrystalline materials were prepared with the solid state method and their structural and phase purity was confirmed by X-ray powder diffraction. Their local crystal structure was studied by high-resolution transmission electron microscopy. The crystal and electronic structure of the nondoped as well as Eu²⁺, R^2+/3+ and other defect containing materials were studied using DFT calculations. The experimental trap depths were obtained using thermoluminescence (TL) spectroscopy. The emission and excitation of Sr₂MgSi₂O₇:Eu²+,Dy³⁺ were also studied. Significant modifications in the local crystal structure due to the Eu²⁺ ion and lattice defects were found by the experimental and DFT methods. The charge compensation effects induced by the R³⁺ co-doping further increased the number of defects and distortions in the host lattice. As for the electronic structure of Sr₂MgSi₂O₇ and SrAl₂O₄, the experimental band gap energy of the host materials was well reproduced by the calculations. The DFT calculated Eu²⁺ and R^2+/3+ 4fn as well as 4f^n-15d¹ ground states in the Sr₂MgSi₂O₇ band structure provide an independent verification for an empirical model which is constructed using rather sparse experimental data for the R³⁺ and especially the R²⁺ ions. The intrinsic and defect induced electron traps were found to act together as energy storage sites contributing to the materials’ efficient persistent luminescence. The calculated trap energy range agreed with the trap structure of Sr₂MgSi₂O₇ obtained using TL measurements. More experimental studies should be carried out for SrAl₂O₄ to compare with the DFT calculations. The calculated and experimental results show that the electron traps created by both the rare earth ions and vacancies are modified due to the defect aggregation and charge compensation effects. The relationships between this modification and the energy storage properties of the solid state materials are discussed.

Targeting of caries prevention at preschool children, a practice based study

Aim and design: To evaluate an oral health program directed to expecting families and their children. The intervention was carried out in one of the four health care areas of the city of Turku. Another area acted as a control. Subjects and methods: Children (n = 1217), born between January 1, 1998 and June 30, 1999, in the respective health care areas were screened for mutans streptococci bacteria (MS), and their caretakers were interviewed when the child was 18 months old. MScolonization was used as the child’s risk indicator. Intensified health education and the use of xylitol lozenges targeted at the children at risk were the main elements of the program. Controls and the non-MS-colonized children received routine prevention –examination and education at the ages of three and five years. Altogether 794 subjects were followed for 42 months after receiving consent from their caretakers. Associations of oral-health-related factors with MS colonization and caries increment were studied inside the control group. Results: MS colonization associated with the occupation of the caretaker and ethnicity. The program was effective in white-collar families; prevented fraction being 67 %. In blue-collar families no effect was achieved. At the age of five years, caries increment was strongly related to the occupation of the caretaker, MS at 18 months, child’s sugar use, night feeding, use of thirst quencher at the age of 18 months, and father’s reported oral health. Conclusions: Programs targeted at MS-colonized children can reduce caries in whitecollar families. A program mainly based on activity at home seems to favor white-collar families, whereas different kind of support is needed for the blue-collar families.

Software Development Process Modeling. Developers Perspective to Contemporary Modeling Techniques

Formal software development processes and well-defined development methodologies are nowadays seen as the definite way to produce high-quality software within time-limits and budgets. The variety of such high-level methodologies is huge ranging from rigorous process frameworks like CMMI and RUP to more lightweight agile methodologies. The need for managing this variety and the fact that practically every software development organization has its own unique set of development processes and methods have created a profession of software process engineers. Different kinds of informal and formal software process modeling languages are essential tools for process engineers. These are used to define processes in a way which allows easy management of processes, for example process dissemination, process tailoring and process enactment. The process modeling languages are usually used as a tool for process engineering where the main focus is on the processes themselves. This dissertation has a different emphasis. The dissertation analyses modern software development process modeling from the software developers’ point of view. The goal of the dissertation is to investigate whether the software process modeling and the software process models aid software developers in their day-to-day work and what are the main mechanisms for this. The focus of the work is on the Software Process Engineering Metamodel (SPEM) framework which is currently one of the most influential process modeling notations in software engineering. The research theme is elaborated through six scientific articles which represent the dissertation research done with process modeling during an approximately five year period. The research follows the classical engineering research discipline where the current situation is analyzed, a potentially better solution is developed and finally its implications are analyzed. The research applies a variety of different research techniques ranging from literature surveys to qualitative studies done amongst software practitioners. The key finding of the dissertation is that software process modeling notations and techniques are usually developed in process engineering terms. As a consequence the connection between the process models and actual development work is loose. In addition, the modeling standards like SPEM are partially incomplete when it comes to pragmatic process modeling needs, like light-weight modeling and combining pre-defined process components. This leads to a situation, where the full potential of process modeling techniques for aiding the daily development activities can not be achieved. Despite these difficulties the dissertation shows that it is possible to use modeling standards like SPEM to aid software developers in their work. The dissertation presents a light-weight modeling technique, which software development teams can use to quickly analyze their work practices in a more objective manner. The dissertation also shows how process modeling can be used to more easily compare different software development situations and to analyze their differences in a systematic way. Models also help to share this knowledge with others. A qualitative study done amongst Finnish software practitioners verifies the conclusions of other studies in the dissertation. Although processes and development methodologies are seen as an essential part of software development, the process modeling techniques are rarely used during the daily development work. However, the potential of these techniques intrigues the practitioners. As a conclusion the dissertation shows that process modeling techniques, most commonly used as tools for process engineers, can also be used as tools for organizing the daily software development work. This work presents theoretical solutions for bringing the process modeling closer to the ground-level software development activities. These theories are proven feasible by presenting several case studies where the modeling techniques are used e.g. to find differences in the work methods of the members of a software team and to share the process knowledge to a wider audience.

Understanding the in vitro dissolution rate of glasses with respect to future clinical applications

Glass is a unique material with a long history. Several glass products are used daily in our everyday life, often unnoticed. Glass can be found not only in obvious applications such as tableware, windows, and light bulbs, but also in tennis rackets, windmill turbine blades, optical devices, and medical implants. The glasses used at present as implants are inorganic silica-based melt-derived compositions mainly for hard-tissue repair as bone graft substitute in dentistry and orthopedics. The degree of glass reactivity desired varies according to implantation situation and it is vital that the ion release from any glasses used in medical applications is controlled. Understanding the in vitro dissolution rate of glasses provides a first approximation of their behavior in vivo. Specific studies concerning dissolution properties of bioactive glasses have been relatively scarce and mostly concentrated to static condition studies. The motivation behind this work was to develop a simple and accurate method for quantifying the in vitro dissolution rate of highly different types of glass compositions with interest for future clinical applications. By combining information from various experimental conditions, a better knowledge of glass dissolution and the suitability of different glasses for different medical applications can be obtained. Thus, two traditional and one novel approach were utilized in this thesis to study glass dissolution. The chemical durability of silicate glasses was tested in water and TRIS-buffered solution at static and dynamic conditions. The traditional in vitro testing with a TRISbuffered solution under static conditions works well with bioactive or with readily dissolving glasses, and it is easy to follow the ion dissolution reactions. However, in the buffered solution no marked differences between the more durable glasses were observed. The hydrolytic resistance of the glasses was studied using the standard procedure ISO 719. The relative scale given by the standard failed to provide any relevant information when bioactive glasses were studied. However, the clear differences in the hydrolytic resistance values imply that the method could be used as a rapid test to get an overall idea of the biodegradability of glasses. The standard method combined with the ion concentration and pH measurements gives a better estimate of the hydrolytic resistance because of the high silicon amount released from a glass. A sensitive on-line analysis method utilizing inductively coupled plasma optical emission spectrometer and a flow-through micro-volume pH electrode was developed to study the initial dissolution of biocompatible glasses. This approach was found suitable for compositions within a large range of chemical durability. With this approach, the initial dissolution of all ions could be measured simultaneously and quantitatively, which gave a good overall idea of the initial dissolution rates for the individual ions and the dissolution mechanism. These types of results with glass dissolution were presented for the first time during the course of writing this thesis. Based on the initial dissolution patterns obtained with the novel approach using TRIS, the experimental glasses could be divided into four distinct categories. The initial dissolution patterns of glasses correlated well with the anticipated bioactivity. Moreover, the normalized surface-specific mass loss rates and the different in vivo models and the actual in vivo data correlated well. The results suggest that this type of approach can be used for prescreening the suitability of novel glass compositions for future clinical applications. Furthermore, the results shed light on the possible bioactivity of glasses. An additional goal in this thesis was to gain insight into the phase changes occurring during various heat treatments of glasses with three selected compositions. Engineering-type T-T-T curves for glasses 1-98 and 13-93 were stablished. The information gained is essential in manufacturing amorphous porous implants or for drawing of continuous fibers of the glasses. Although both glasses can be hot worked to amorphous products at carefully controlled conditions, 1-98 showed one magnitude greater nucleation and crystal growth rate than 13-93. Thus, 13-93 is better suited than 1-98 for working processes which require long residence times at high temperatures. It was also shown that amorphous and partially crystalline porous implants can be sintered from bioactive glass S53P4. Surface crystallization of S53P4, forming Na2O∙CaO∙2SiO2, was observed to start at 650°C. The secondary crystals of Na2Ca4(PO4)2SiO4, reported for the first time in this thesis, were detected at higher temperatures, from 850°C to 1000°C. The crystal phases formed affected the dissolution behavior of the implants in simulated body fluid. This study opens up new possibilities for using S53P4 to manufacture various structures, while tailoring their bioactivity by controlling the proportions of the different phases. The results obtained in this thesis give valuable additional information and tools to the state of the art for designing glasses with respect to future clinical applications. With the knowledge gained we can identify different dissolution patters and use this information to improve the tuning of glass compositions. In addition, the novel online analysis approach provides an excellent opportunity to further enhance our knowledge of glass behavior in simulated body conditions.